This invention relates to drug formulations in form of tablets for oral administration from which a non-moisture sensitive, physiologically acceptable salt of tramadol is released in a sustained manner and which contain at least one pharmaceutically acceptable matrixing agent.
Tramadolhydrochloride-(1RS;2RS)-2-[(dimethylamino)methyl]-1-(3-methoxypheny l)cyclohexanol, hydrochloride--is an analgesic effective in severe and moderate severe pain. All drug formulations available on the market are immediate release forms which require administration 3 to 4 times per day in order to achieve good therapeutic effectiveness in relieving chronic pain. It would be a desirable relief to the patients if the frequency of administration could be reduced to once or twice daily.
Several principles of sustained release formulations are known to a person skilled in the art. For example, U.S. Pat. No. 3,065,143, filed on Apr. 19, 1960, discloses a sustained release tablet containing at least one-third part by weight of the weight of the tablet of a pharmaceutically acceptable hydrophilic gum which rapidly absorbs water and swells at 37.degree. C. to form a soft mucilaginous gel barrier on the surface of the tablet when brought into contact with the aqueous fluids of the gastrointestinal tract which prevents rapid disintegration of the tablet and release of the medicament contained therein when taken orally, but allows slow disintegration of the tablet and release of medicament over a period of at least four hours. However, the examples show that the release of the medicament is influenced by the pH value. For the release mechanism it is further described that the soft mucilaginous gum gel barrier is worn away by the motion of the tablet in the gastrointestinal tract, and some of the admixed medicinal agent is carried away with it and released. At the same time the protective coating at the surface of the tablet is renewed. This means that the release of the medicament is also influenced by mechanical stress. Further it is described that the rate of release depends on the weight ratio of active ingredient to gum as well as on the content of hydrophilic gum in the tablet.
In U.S. Pat. No. 4,389,393 (Reexamination Certificate B1 4,389,393) a carrier base material for moisture sensitive active ingredients is disclosed which is shaped and compressed to a solid unit dosage form and has a regular and prolonged release pattern upon administration. The carrier base material consists of one or more hydroxypropylmethylcelluloses or a mixture of one or more hydroxypropylmethylcelluloses and up to 30% by weight of the mixture of methylcellulose, sodium carboxymethylcellulose and/or other cellulose ether, wherein at least one of the hydroxypropylmethylcelluloses has a methoxy content of 16-24% by weight, a hydroxypropyl content of 4-32% by weight and a number average molecular weight of at least 50,000. The carrier base material constitutes 30% by weight or less of the solid unit dosage form and causes that at least four hours are required for the release of 94.4% of the moisture sensitive active ingredient from the dosage form following administration.
In Int. J. Pharm. Tech. & Prod. Mfr. 5, 1 (1984) hydrophilic matrices, especially hydroxypropylmethylcelluloses, are described for oral dosage forms with controlled release. On pages 4 to 6 it is explained that the rate of drug release depends on the viscosity as well as on the amount of the employed polymer. Furthermore size and shape of the dosage unit influence the release, whereas practically no dependence on the manufacturing process by granulation or by direct tabletting is observed. On the other hand different fillers show a pronounced influence on the drug release. According to FIGS. 16 and 18, insoluble excipients cause an acceleration of the release up to complete suppression of the controlled release effect, independent of whether these compounds are swellable such as microcrystalline cellulose or are not swellable such as calcium hydrogen phosphate.
From Int. J. Pharm. 40, 223 (1987) it is known that the rate of drug release from a sustained release tablet containing hydroxypropylmethylcellulose as the matrixing agent depends on the weight ratio of active substance to hydroxypropylmethylcellulose. The more this ratio is shifted in favor of the active substance, the higher the rate of release. In formulations having a filler content which is more than 50% by weight, the rate of release is influenced by the types of adjuvants employed. A partial replacement of hydroxypropylmethylcellulose with a filler and a consequent reduction of the hydroxypropylmethylcellulose content in the dosage form leads to an increase in the release rate.
The matrix sustained release tablets described in J. Pharm. Sci. 57, 1292 (1968) lead to an increased release rate when increasing the soluble portions in the hydrophilic matrix.